Clinical Investigations

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1 Clinical Investigations Deeply Reinverted T Wave at 14 Days After the Onset of First Anterior Acute Myocardial Infarction Predicts Improved Left Ventricular Function at 6 Months Address for correspondence: Ken Okumura, MD, Department of Cardiology, Hirosaki University Graduate School of Medicine, Zaifu-cho 5, Hirosaki , Japan, okumura@cc.hirosaki-u.ac.jp Hiroaki Yokoyama, MD; Hirofumi Tomita, MD; Fumie Nishizaki, MD; Kenji Hanada, MD; Shuji Shibutani, MD; Masahiro Yamada, MD; Naoki Abe, MD; Takumi Higuma, MD; Tomohiro Osanai, MD; Ken Okumura, MD Department of Cardiology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan Background: Changes in electrocardiogram (ECG), especially in the ST segment and T wave, have been recognized as a noninvasive diagnostic tool for coronary flow or myocardial injury. Hypothesis: A deeply inverted T wave at 14 days after successful percutaneous coronary intervention (PCI) in patients with ST-segment elevation acute myocardial infarction (STEMI) predicts improved left ventricular (LV) function at 6 months. Methods: We enrolled 112 consecutive patients (88 men, 63 ± 11 years) with first anterior STEMI who underwent successful PCI. A 12-lead ECG was recorded everyday from admission through 14 days. After PCI, the first T-wave inversion was observed within 2 days, and the second occurred at 14 days. We measured the maximum depth of the reinverted T wave (Neg-T) and divided the patients into 2 groups based on the median value of Neg-T: the deep group ( 0.6 mv, n = 62) and the nondeep group (<0.6 mv, n = 50). Results: LV ejection fraction (LVEF) at 14 days did not differ between the 2 groups, but it was greater in the deep than in the nondeep group at 6 months (50.0% ± 8.8% vs 42.5% ± 9.8 %, P < ). The maximum creatinine phosphokinase-myocardial band (CPK-MB) value was significantly lower in the deep than in the nondeep group. Reappearance of the R wave in precordial leads at 6 months was more frequently observed in the deep than in the nondeep group (68% vs 46%, P = 0.02). Multivariate regression analysis showed that the Neg-T and max CPK-MB were independent contributors to LVEF at 6 months. Conclusions: A deeply reinverted T wave at 14 days after onset of first anterior STEMI can be a useful predictive marker for improved LV function at 6 months. Introduction Revascularization therapy such as percutaneous coronary intervention (PCI) is the effective treatment that reduces not only hospital mortality but long-term mortality in patients with ST-segment elevation myocardial infarction (STEMI). 1 Accumulating evidence demonstrates the diagnostic efficacy of electrocardiogram (ECG) monitoring in patients with acute myocardial infarction (AMI) after revascularization therapy, and changes in ECG, especially in ST segment and T wave, have been recognized as a functional marker of coronary flow or myocardial injury in the acute phase of AMI. 2 Previous studies have focused on such dynamic changes within the first few days after reperfusion therapy. The authors have no funding, financial relationships, or conflicts of interest to disclose. Additional Supporting Information may be found in the online version of this article. Received: August 7, 2014 Accepted with revision: November 8, 2014 Cortadellas et al reported that ST-segment elevation in first anterior STEMI patients at 72 hours after admission correlates negatively with left ventricular ejection fraction (LVEF) at 1 year after AMI. 3 We also previously reported that re-elevation of the T wave from day 2 to day 4 after successful PCI predicts chronic cardiac systolic dysfunction in patients with first anterior STEMI. 4 We further showed that T-wave inversion occurs not only within 24 hours after reperfusion therapy but at approximately 14 days after the onset. 4 However, there are few studies that evaluate the relationship between a reinverted T wave at 14 days and left ventricular (LV) function in the chronic phase. In the present study, we investigated whether a deeply inverted T wave at 14 days after the onset predicts LV function in the chronic phase in patients with first anterior STEMI. Methods Study Patients We prospectively enrolled 112 consecutive patients (88 males; age, 63 ± 11 years) with first anterior STEMI 157

2 admitted to the Hirosaki University Hospital. All patients underwent emergent coronary angiography and successful reperfusion therapy to the left anterior descending artery (LAD) by PCI with a bare-metal stent within 24 hours after the onset. STEMI was diagnosed by an episode of a typical chest pain continuing over 30 minutes associated with ST-segment elevation at the J point in 2 or more precordial leads, and an increased plasma level of creatinine phosphokinase-myocardial band (CPK-MB) 2 times higher than the normal upper limit. 5 Patients who had previous myocardial infarction evaluated by both ECG and their history, left bundle branch block, ventricular pacing, or treatment with drugs having potential effects on ECG such as antiarrhythmics were excluded. This study was approved by the ethics committee of our institution. Electrocardiographic Evaluation A standard 12-lead ECG was recorded on admission and everyday from the day immediately following PCI (day 0) through day 14 at predischarge. Patients with STEMI after PCI in Japan are generally hospitalized for approximately 14 days for acute therapy and subsequent cardiac rehabilitation. The maximum depth of the inverted T wave from the isoelectric line, defined as a level of the preceding TP segment, was measured with handheld calipers. The depths as a mean of 3 successive beats were measured in all precordial leads each time, and the maximum depth was determined among them, mostly in lead V2 or V3. The maximum level of ST-segment elevation at 80 ms after the J point was also determined. Furthermore, the number of precordial leads with abnormal Q wave or QS pattern was counted. QRS magnitude was determined by the following: amplitude of the R wave was subtracted by the greater depth of either the Q or S wave in the lead where the maximum depth of the reinverted T wave was observed. ECG evaluations were performed by 2 cardiologists blinded to all clinical and angiographic findings. Left Ventricular Function and Coronary Artery Flow Cardiac catheterization including coronary angiography and left ventriculography (LVG) to evaluate stent condition and LV function were performed at approximately 14 days (subacute phase) and 6 months (chronic phase) after the onset as well as in the acute phase. This schedule for cardiac catheterization is commonly accepted in Japan and was approved by the ethics committee of our institution. We measured LVEF and LV end-diastolic volume index (LVEDVI) by LVG with the right anterior oblique view. Changes in LVEF and in LVEDVI between subacute and chronic phases were calculated. Coronary blood flow was evaluated using the Thrombolysis In Myocardial Infarction (TIMI) scale, 6 and all patients had a final TIMI grade of II or III in the acute phase. We further evaluated retrograde collateral flow to the LAD in the acute phase as follows (Rentrop s grade): 0 (none), 1 (filling of side branches of the artery without visualization of the epicardial segment), 2 (partial filling of the epicardial segment), and 3 (complete filling of the epicardial segment). 7 All patients, regardless of TIMI flow, received oral antiplatelet drugs including low-dose aspirin and clopidogrel or ticlopidine. The cardiovascular events such as myocardial infarction recurrence, stroke, heart failure, and life-threatening ventricular arrhythmias were also evaluated at 6 months. Blood Samples Blood samples were taken from all patients, and plasma levels of creatinine phosphokinase (CPK), CPK-MB, and brain natriuretic peptide (BNP) were measured in our hospital chemistry laboratory using standard techniques. BNP levels were also measured at 14 days and 6 months. Statistical Analysis All variables were expressed as mean ± standard deviation. The unpaired t test or χ 2 test was used to compare the differences between 2 groups. Mann Whitney U test was used for nonparametric variables. A linear Pearson or Spearman rank correlation analysis was performed for correlation studies. Multivariate regression analyses were performed for the LVEF at 6 months and the maximum depth of T-wave reinversion at 14 days. Statistical analyses were performed using JMP 10 software (SAS, Cary, NC). A P value of < 0.05 was considered statistically significant. Results Time Course of ECG Changes Representative serial ECG changes are shown in Figure 1A. After reperfusion, resolution of ST elevation and T-wave inversion were observed in all patients within 2 days after PCI. Of them, 107 patients (96%) showed re-elevation of the T wave within 5 days from the onset. Importantly, they all showed T-wave inversion again at approximately 14 days after the onset. Relationships Between Maximum Depth of T-Wave Reinversion and Baseline Characteristics of the Patients To assess the clinical significance of T-wave reinversion at 14 days after the onset, we evaluated relationships between the maximum depth of T-wave reinversion and the clinical characteristics of the patients. For this purpose, the patients were divided into 2 groups according to the value (0.6 mv) of the maximum depth of T-wave reinversion (Neg-T) at 14 days after the onset: deep group (Neg-T 0.6 mv, n = 62) and nondeep group (Neg-T < 0.6 mv, n = 50). The value (0.6 mv) was determined based on our previous analysis (data not shown) 4 and its median value in the present study. Representative ECG in each group is shown in Figure 1B. There were no significant differences in the following baseline characteristics between the 2 groups: age, coronary risk factors, blood chemistry, and reperfusion time from the onset (Table 1). More female patients and greater body mass index (BMI) were found in the nondeep group. Killip classification, initial and final TIMI grades, and retrograde collateral flow to the LAD did not differ between the 2 groups. Drug therapy such as β-blockers and angiotensin I-converting enzyme inhibitors or angiotensin II type I receptor blockers at discharge was not different between the 2 groups. The severity of myocardial infarction assessed by maximum CPK-MB level was lower in the deep group 158 DOI: /clc Wiley Periodicals, Inc.

3 (A) (B) Figure 1. (A) A typical time course of a precordial electrocardiogram (ECG) recording in a patient with a first anterior ST-elevation acute myocardial infarction who had undergone successful percutaneous coronary intervention (PCI). The ECG shows ST-segment elevation at admission, ST-segment resolution and T-wave inversion at 2 days after successful PCI, ST-segment re-elevation at 5 days, and T-wave inversion again (reinversion) at 14 days. (B) Representative precordial ECG recording at 14 days after the onset of acute myocardial infarction in patients in the deep group and the nondeep group. than in the nondeep group (330 ± 191 vs 426 ± 236 IU/L, P =.018) (Table 1), although the maximum CPK level was not significantly different. Comparisons of Cardiac Function, Plasma BNP, and ECG Variables Between the Two Groups We compared the LV function assessed by LVG between the 2 groups at 14 days and at 6 months (Table 2). Although LVEF at 14 days did not differ between the 2 groups, LVEF at 6 months was significantly greater in the deep group than in the nondeep group (50.0% ± 8.8% vs 42.5% ± 9.8%, P < ). An increased change in LVEF between 14 days and 6 months ( LVEF) in the deep group supports this finding (5.1% ± 10.4% vs 0.1% ± 9.7%, P = 0.002). In contrast, LVEDVI at both 14 days and 6 months, and its change ( LVEDVI) were similar between the 2 groups, suggesting no significant effect of T-wave reinversion on LV remodeling. Plasma BNP level at 14 days was not different between the 2 groups, whereas at 6 months plasma BNP level was lower in the deep group, although not significant between the 2 groups. Being consistent with this finding, a greater change in plasma BNP level ( BNP) was found in the deep group than in the nondeep group ( 107 ± 225 vs 5 ± 204 pg/ml, P = 0.01). All these findings suggest that LV function in the deep group was improved in the chronic phase compared with that in the nondeep group. We further compared ECG variables between the 2 groups (Table 2). The Neg-T in the deep group was remarkably improved at 6 months compared with that in the nondeep group, as assessed by its change between 14 days and 6 months ( Neg-T, 0.74 ± 0.51 vs 0.17 ± 0.21 mv, P < ). Importantly, although the number of leads with Q wave or QS pattern was similar between the 2 groups at 14 days and at 6 months, the number of leads with Q wave or QS pattern was 2 times decreased in deep group than in the nondeep group at 6 months ( number of Q or QS, 1.21 ± 1.36 vs 0.62 ± 0.92, P = 0.01). Furthermore, reappearance of the R wave in precordial leads at 6 months was more frequently observed in the deep group than in the nondeep group (68% vs 46%, P = 0.02). The maximum level of ST-segment elevation at 14 days and at 6 months, and its change, did not differ between the 2 groups. Factors Contributing to the Depth of T-Wave Reinversion at 14 Days Analyses to determine factors associated with the maximum depth of T-wave reinversion at 14 days were performed (see Supporting Table 1 in the online version of this article). Univariate regression analysis showed that only BMI was negatively correlated with it (r = 0.20, P = 0.03), but not age, gender, maximum level of ST-segment elevation, the number of precordial leads with abnormal Q wave or QS pattern, and QRS magnitude. Multivariate analysis further showed that BMI was an independent predictor for maximum depth of T-wave reinversion at 14 days (β = 0.22, standard error of the mean = 0.01, P = 0.03). There were no patients with chronic obstructive pulmonary disease and no patients with a strain pattern of ST-T change that characterizes LV hypertrophy. No difference in patients with complete right bundle branch block was found between the deep and nondeep groups (5 [8%] vs 5 [10%], P = 0.75). We further evaluated relationship between the maximum level of re-elevation of the T wave at 5 days and reinversion of the T wave at 14 days. We found that the maximum level of re-elevation of the T wave at 5 days was lower in the deep group than in the nondeep group (0.51 ± 0.21 vs 0.61 ± 0.23 mv, P = 0.03). Furthermore, re-elevation of the T wave at 5 days was weakly and negatively correlated with the maximum depth of T-wave reinversion at 14 days (r = 0.20, P = 0.04). Relationships Between the Maximum Depth of T-Wave Reinversion and Chronic Cardiac Function To assess the clinical significance of T-wave reinversion, we evaluated relationships between the maximum depth of 159

4 Table 1. Baseline Characteristics of the Study Patients Table 1. Continued Deep n = 62 Nondeep n = 50 P Value Deep n = 62 Nondeep n = 50 P Value Age, y 62 ± ± Gender, female (%) 8 (13%) 16 (32%) 0.02 BMI, kg/m ± ± Risk factors, n (%) Hypertension 28 (45%) 31 (62%) 0.09 Dyslipidemia 32 (52%) 28 (56%) 0.71 Diabetes mellitus 26 (42%) 22 (44%) 0.85 Smoking 41 (66%) 30 (60%) 0.56 Blood chemistry Total cholesterol, mg/dl 184 ± ± Triglyceride, mg/dl 81 ± 44 92± LDL cholesterol, mg/dl 120 ± ± HDL cholesterol, mg/dl 47 ± ± Glucose, mg/dl 134 ± ± HbA1c, % 5.7 ± ± Maximum CPK, IU/L 3802 ± ± Maximum CPK-MB, IU/L 330 ± ± Killip classification, n (%) 0.28 I 56 (90%) 43 (86%) II 4 (6%) 6 (12%) III/IX 2 (3%) 1 (2%) Time to reperfusion, h 6.2 ± ± Medication, n (%) β-blockers 58 (94%) 49 (98%) 0.38 ACE-I/ARB 53 (85%) 39 (78%) 0.33 Collateral flow, n (%) /I 52 (84%) 46 (92%) II 7 (11%) 3 (6%) III 3 (5%) 1 (2%) TIMI grade before PCI, n (%) /I 42 (68%) 42 (84%) II 19 (31%) 8 (16%) III 1 (2%) 0 (0%) TIMI grade after PCI, n (%) /I 0 (0%) 0 (0%) II 7 (11%) 8 (16%) III 55 (89%) 42 (84%) Abbreviations: ACE-I, angiotensin I-converting enzyme inhibitor; ARB, angiotensin II type I receptor blocker; BMI, body mass index; CPK- MB, creatinine phosphokinase-myocardial band; Hb1Ac, hemoglobin A1c; HDL, high-density lipoprotein; LDL, low-density lipoprotein; PCI, percutaneous coronary intervention; TIMI, Thrombolysis In Myocardial Infarction. Values are shown as mean ± standard deviation or n (%). T-wave reinversion and chronic cardiac function. The maximum depth of T-wave reinversion was negatively correlated with the maximum CPK-MB value (r = 0.28, P = 0.003, Figure 2A), and positively with LVEF at 6 months (r = 0.37, P < , Figure 2B). It was also positively correlated with LVEF (r = 0.27, P = 0.004, Figure 2C), and negatively with BNP (r = 0.23, P = 0.016, Figure 2D). These findings indicate that patients with a deeper reinverted T wave at 14 days had a relatively smaller infarct size and an improved chronic LV function. Furthermore, the maximum level of ST-segment elevation and the number of leads with Q wave or QS pattern at 14 days were both negatively correlated with LVEF at 6 months (r = 0.21, P = 0.03, and ρ = 0.31, P = , respectively). Multivariate regression analysis showed that the maximum depth of T-wave reinversion at 14 days and maximum CPK-MB value were independent contributors to the LVEF at 6 months after adjusting age, BMI, and gender, but the maximum level of ST-segment elevation and the number of leads with Q wave or QS pattern at 14 days were not (Table 3). Finally, we evaluated cardiovascular events at 6 months and found that there were no differences in any events at 6 months between the 2 groups (see Supporting Table 2 in the online version of this article). Discussion In the present study, we assessed serial daily changes in 12- lead ECGs in patients with first anterior STEMI successfully treated with PCI in the acute phase. We found the dynamic ECG changes after successful PCI, which showed that the ST-segment elevation at admission is followed by the inversion of the T wave within 2 days after PCI, re-elevation of the T wave within 5 days, and the reinversion of the T wave at 14 days. To further evaluate clinical significance of these ECG changes, patients were divided into 2 groups based on the maximum depth of T-wave reinversion at 14 days: the deep group (Neg-T 0.6 mv) and the nondeep group (Neg- T < 0.6 mv). The analyses showed that the deep group patients had a smaller infarct size and a more improved chronic LV function than the nondeep group, and that a deeper reinverted T wave was an independent contributor to increased LVEF in the chronic phase. Furthermore, ECGs at 6 months showed more reappearance of the R wave in the deep than in the nondeep group. To the best of our 160 DOI: /clc Wiley Periodicals, Inc.

5 Table 2. Left Ventricular Function, Plasma Brain Natriuretic Peptide Level, and Electrocardiogram Variables at 14 Days and 6 Months Subacute phase (14 days) Deep n = 62 Nondeep n = 50 P Value LVEF (%) 44.9 ± ± LVEDVI (ml/m 2 ) 85.5± ± BNP (pg/ml) 198 ± ± Chronic phase (6 months) LVEF (%) 50.0 ± ± 9.8 < LVEDVI (ml/m 2 ) 91.7 ± ± BNP (pg/ml) 91 ± ± Changes (6 months 14 days) LVEF (%) 5.1 ± ± LVEDVI (ml/m 2 ) 6.2± ± BNP (pg/ml) 107 ± ± ECG variables (14 days) Neg-T (mv) 0.98 ± ± 0.12 < Maximum ST level (mv) 0.22 ± ± No. of Q or QS 3.5 ± ± ECG variables (6 months) Neg-T (mv) 0.28 ± ± Maximum ST level (mv) 0.17 ± ± No. of Q or QS 2.2 ± ± Reappearance of R wave, n (%) 42 (68%) 23 (46%) 0.02 Changes (6 months 14 days) Neg-T (mv) 0.74 ± ± 0.21 < Maximum ST level (mv) 0.05 ± ± No. of Q or QS 1.21 ± ± Abbreviations: BNP, brain natriuretic peptide; ECG, electrocardiogram; LVEF, left ventricular ejection fraction; LVEDVI, left ventricular end-diastolic volume index; Maximum ST level, maximum level of ST-segment elevation at 80 ms after the J point; Neg-T, maximum depth of T-wave reinversion; No. of Q or QS, the number of precordial leads with abnormal Q wave or QS pattern. Values are shown as mean ± standard deviation or n (%). knowledge, this is the first study showing that reinversion of the T wave at 14 days after successful PCI can be a useful predictive marker for improved LV function at 6 months after the onset of AMI. Numerous studies have shown that early ST resolution within 24 hours after reperfusion therapy in patients with first anterior STEMI is associated with a reduced infarct size and better LV function. 3,8 13 Of them, some studies showed that no ST resolution occurs in 20% to 35% of patients with AMI after PCI, 8,9 in which the ECG was examined at just 1 point, immediately or 30 minutes after PCI. In contrast, we examined ECGs every day showing that all patients had ST resolution within 2 days after successful PCI with a stent. Our previous study further confirmed that the deepest T wave was observed at 2 days after successful PCI. 4 These indicate that the timing of the examination ECG may be important for evaluating ST resolution. However, little attention has been paid to the clinical significance of T-wave reinversion at 14 days after the onset of AMI. Nakajima et al reported a biphasic pattern of T-wave inversion in patients with anterior AMI, which is the first negative peak occurring about 48 hours and the second negative peak about 18 days after the onset. 14 They found that the depth of the inverted T wave at 48 hours after the onset was negatively correlated with the extent of LV hypokinesis in the chronic phase, suggesting that the deeper inverted T wave in the early phase can be a better clinical marker for chronic LV wall motion. However, no significant correlation was found between the depth of the second inverted T wave at 18 days and the extent of LV hypokinesis, possibly due to a small study population (n = 43). In contrast, our study, with more patients, showed a significant positive correlation between the depth of the reinverted T wave and chronic LVEF, which was also supported by the multivariate regression analysis. Accordingly, our findings provide an important clinical significance of reinverted T wave at 14 days after the onset of AMI for chronic LV function. The mechanism by which the deep group of patients showed a greater LVEF in the chronic phase than the nondeep group is less obvious and cannot be fully elucidated from the present study. However, the lower maximum CPK-MB level in the deep group suggests that the deep group had a smaller infarct size. A previous report showed that the amount of myocardium at risk, collateral flow, and duration of coronary occlusion are each independently associated with infarct size. 15 In the present study, we found no differences in collateral flow to the LAD or in time to reperfusion therapy (PCI) between the 2 groups; therefore, the amount of myocardium at risk, which can be evaluated by technetium sestamibi, may be associated with the smaller infarct size in the deep group. Although it is of considerable interest to investigate relationships between reinverted T wave at 14 days and the amount of myocardium at risk, further clinical studies are required in this regard. Moreover, the present study showed that BMI was an independent negative predictor for maximum depth of T-wave reinversion at 14 days, but not for chronic LV function, suggesting that BMI may simply influence T-wave reinversion but not to LV function. It has been reported that the presence of isoelectric ST segment and negative T wave at approximately 1 week after the onset of AMI predicts a high probability of myocardial viability, as assessed by low-dose dobutamine stress echocardiography. 11,16 This supports our finding that the deep group had a more improved chronic LV function. Therefore, reinverted T waves may be indicative of a residual myocardial viability, and patients with a deeply reinverted T wave at 14 days may have more stunned myocardium. The number of leads with a Q wave or QS pattern at 6 months was lower in the deep group, and the reappearance of the R wave 161 DOI: /clc Wiley Periodicals, Inc.

6 (A) (B) (C) (D) Figure 2. Relationships between maximum depth of T-wave reinversion (Neg-T) and maximum creatinine phosphokinase-myocardial band (CPK-MB) level (A), left ventricular ejection fraction (LVEF) at 6 months (B), changes in LVEF between 14 days and 6 months ( LVEF) (C), and changes in plasma brain natriuretic peptide (BNP) level between 14 days and 6 months ( BNP) (D). Table 3. Multivariate Regression Analysis for Left Ventricular Ejection Fraction at Six Months Coefficient (β) SEM P Value Age BMI Gender (female) Neg-T at 14 days Maximum ST level at 14 days No. of Q or QS at 14 days Max CPK-MB BNP at 14 days Abbreviations: BMI, body mass index; BNP, brain natriuretic peptide; CPK-MB, creatinine phosphokinase-myocardial band; Maximum ST level, maximum level of ST-segment elevation at 80 ms after the J point; Neg-T, maximum depth of T-wave reinversion; No. of Q or QS, the number of precordial leads with abnormal Q wave or QS pattern; SEM, standard error of the mean. at 6 months was higher in deep group than in the nondeep group in the present study. In addition, the amplitude of the re-elevated T wave at 5 days was negatively correlated with the depth of the reinverted T wave at 14 days. All of these findings suggest involvement of a repolarization process in ECG changes and consequently in improved chronic LV function. There are some limitations in this study. First, our results are derived from the relatively small number of study patients and a single-center analysis, therefore generalization of our results would be limited. Second, our findings can be applied only to the anterior AMI patients. The analyses of ECGs in patients with AMI that occurred in other regions are of interest. Finally, the precise mechanism by which the reinverted T wave is observed at 14 days in AMI patients treated with successful PCI remains largely uncertain in the present study. Despite these limitations, our evaluation of negative T wave at 14 days after AMI onset appears to be a useful method to predict an improved LV function in the chronic phase. Further large-scale clinical studies are needed. Conclusion We provide evidence that patients with a deeply reinverted T wave at 14 days after AMI onset have a smaller infarct size and a more improved chronic LV function. Because the degree of reinversion of the T wave was correlated with LV function and was an independent predictor of LVEF in the chronic phase, the reinverted T wave at 14 days after successful PCI can be a clinically useful prognostic marker for patients with AMI. 162

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